6OR1

Human LRH-1 bound to the agonist 2N and a fragment of the Tif2 coregulator

Summary for 6OR1

• Entry DOI: 10.2210/pdb6or1/pdb
• Descriptor: Nuclear receptor subfamily 5 group A member 2, Nuclear receptor coactivator 2, N-[(1S,3aR,6aR)-5-hexyl-4-phenyl-3a-(1-phenylethenyl)-1,2,3,3a,6,6a-hexahydropentalen-1-yl]acetamide, ... (4 entities in total)
• Functional Keywords: nuclear receptor, coactivator, agonist, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30568.35

Authors

Mays, S.G.,Ortlund, E.A. (deposition date: 2019-04-29, release date: 2019-08-28, Last modification date: 2023-10-11)

Primary citation

Mays, S.G.,Flynn, A.R.,Cornelison, J.L.,Okafor, C.D.,Wang, H.,Wang, G.,Huang, X.,Donaldson, H.N.,Millings, E.J.,Polavarapu, R.,Moore, D.D.,Calvert, J.W.,Jui, N.T.,Ortlund, E.A.
Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design.
J.Med.Chem., 62:11022-11034, 2019

PubMed Abstract: As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, liver receptor homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases (IBD). Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of IBD, the new agonist increases expression of LRH-1-controlled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.

PubMed: 31419141
DOI: 10.1021/acs.jmedchem.9b00753

Experimental method

X-RAY DIFFRACTION (2.174 Å)